PROJECT SUMMARY Schizophrenia (SCZ) is a profoundly disabling neurodevelopmental disorder causing marked functional impairment. SCZ is hypothesized to arise from synaptic disturbances affecting large-scale neural connectivity along cortico?thalamic- striatal?cortical (CTSC) pathways. Neuroimaging evidence supports this view by showing alterations in associative cortices and connectivity disruptions across CTSC circuits in chronic SCZ. Yet, the complex evolving neurobiology of early-course SCZ remains uncharacterized. This limits treatments for early illness phases when intervention is crucial by capitalizing on the narrow `window' of opportunity to halt disease progression. Thus, understanding the neurobiology of early-course SCZ is a major objective for early detection, prognosis prediction and targeted individualized therapy. A major complicating factor in many SCZ studies is the confounding presence of antipsychotic treatment. Thus, our goal is to characterize co-occurring functional and structural dysconnectivity in unmedicated early-course SCZ and quantify neural changes in relation to cardinal SCZ symptoms, cognitive deficits and treatment response. To achieve this, we will examine longitudinal progression of neural dysconnectivity in 150 unmedicated early-course SCZ patients after their initial admission into clinics affiliated with West China Hospital. We will follow patients longitudinally at 6, 12, and 24 months later in comparison with 150 matched healthy controls. We will use state-of-the-art functional and structural methods optimized by the Human Connectome Project to achieve cutting-edge multi-modal neuroimaging integration. As noted, mounting evidence implicates CTSC loops in SCZ, particularly higher-order prefrontal and thalamic regions (e.g. medio-dorsal structures), suggesting mechanistic links between CTSC dysfunction and SCZ symptoms. Thus, first we aim to test if the identified CTSC markers exhibit concurrent (or dissociable) structural and functional alterations in unmedicated SCZ patients and if these circuits alter longitudinally. Second, we will test if structural and functional neuroimaging alterations relate to severity of cardinal SCZ symptoms and cognitive deficits. This provides a much-needed mapping between longitudinal CTSC dysconnectivity, symptoms and cognition in SCZ. Critically, this balanced longitudinal design can distinguish `state' versus `trait' neuroimaging markers during early illness course in relation to clinically relevant variables. Finally, it is well established that many SCZ patients do not respond well to antipsychotics. Yet, the neural markers of poor treatment response remain unmapped (and conversely treatment response). A key advantage of the proposed U.S.-China partnership is precisely the capacity to longitudinally study large sample sizes starting from medication-free observations, afforded by extensive and robust recruitment infrastructure at West China Hospital. Thus, our third aim is to quantify longitudinal structural and functional CTSC dysconnectivity in relation to treatment response. Collectively, this study will map longitudinal `state' versus `trait' neural markers starting from medication-free early illness stages (Aim 1), relate these changes to symptom dynamics (Aim 2) and treatment response (Aim 3). This mapping is vital to inform future work aimed at maximizing individualized early intervention strategies.